Human herpesvirus-8 (HHV-8) encodes several proteins that have been implicated in virus-associated pathogenesis. Chief among these is the chemokine receptor (vGPCR) specified by ORF74, which has mitogenic and angiogenic properties, promotes cell transformation and tumor growth in in vitro and in vivo experimental systems. However, little is known about the function of the HHV-8 heptahelical receptor in normal virus biology. This application focuses on the role of vGPCR in virus lytic replication, and in particular on the likely relevance of vGPCR-induced survival signaling to enhancement of virus production. The hypothesis that vGPCR-mediated survival signaling contributes to efficient virus replication is based in part on our finding that HHV-8 chemokines vCCL-1 and vCCL-2 mediate these activities in endothelial cells, via cellular GPCR CCR8. It is also supported by the known pro-survival activities of vGPCR and our demonstration using BAC36-HHV-8 genome-based ORF74 disruption and shRNA-mediated vGPCR depletion in infected PEL and endothelial cells that vGPCR is required for efficient virus productive replication. The specific aims are: (1) to characterize vGPCR survival signaling in endothelial cells and the pathways and mechanism involved;(2) to determine the operation and relevance to virus productive replication of these pathways in the context of HHV-8-infected endothelial cells;(3) to elucidate the contributions to pro-survival signaling and virus replication of cellular cytokines induced by vGPCR during lytic replication. This study will, for the first time, characterize the role of vGPCR in virus biology, specifically the relevance of vGPCR-mediated survival signaling to virus productive replication. The results will be of significance in consideration of vGPCR and downstream effectors as targets for anti-viral and disease therapy.